Metabolic diseases associated with abnormal metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality. Several members of the nuclear receptor (NR) superfamily regulate the expression of key genes involved in regulation of carbohydrate and lipid metabolism in response to their ligands, which include fatty acids, bile acids, cholesterol metabolites, steroid hormones, and lipophilic vitamin derivatives. We have identified the first synthetic ligands that target the retinoic acid receptor- related orphan receptors (RORa, and RORy), receptors that are well characterized for their ability to modulate glucose and lipid metabolism. This is an application for a R24 grant titled, "Seeding Collaborative Interdisciplinary Team Science in Diabetes, Endocrinology and l\/letabolic Diseases", and the focus of our proposed research is to enable our research team consisting of NR pharmacology, structural biology, metabolic disease pharmacology, drug metabolism and pharmacokinetics, and medicinal chemistry to focus on development of orally active ROR ligands for the treatment of diabetes arid/or obesity. These studies are essential for our understanding of how synthetic ROR ligands might coordinate metabolic pathways and more generally, determination of whether or not ROR ligands may be useful in the treatment of metabolic syndrome. RELEVANCE: Our proposed studies to develop ROR targeted drugs may provide the basis for novel therapeutics targeting the RORs for treatment of metabolic disorders such as diabetes, atherosclerosis and obesity.